Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized steatosis and inflammation. The transition from steatosis towards NASH a key step in pathogenesis, as it will set the stage for further severe damage. Under normal conditions, lipoproteins that are endocytosed by cells (KCs) are easily transferred from the lysosomes into the Oxidized LDL (oxLDL) that is taken up by the macrophages in vitro is within the lysosomes, while acetylated LDL (acLDL) is leading to normal hydrolysis, resulting in cytoplasmic storage. We have recently hepatic inflammation is correlated with lysosomal trapping of lipids. So link between lysosomal trapping of oxLDL and inflammation was not hypothesized that lysosomal trapping of oxLDL in KCs will lead to inflammation. METHODS: Ldlr-/- mice were injected with LDL, acLDL and sacrificed after 2, 6 and 24 h. RESULTS: Electron microscopy of KCs that after oxLDL injection, small lipid inclusions were present inside lysosomes after all time points and were mostly pronounced after 6 and contrast, no lipid inclusions were present inside KCs after LDL or acLDL injection. Hepatic expression of several inflammatory genes and receptors was higher after oxLDL injections compared with LDL or acLDL. CONCLUSIONS: These data suggest that trapping of oxLDL inside lysosomes vivo is causally linked to increased hepatic inflammatory gene novel observations provide new bases for prevention and treatment of